HDACs are zinc metalloenzymes that catalyse the hydrolysis of acetylated lysine residues. In histones, this returns lysines to their protonated state and is a global mechanism of eukaryotic transcriptional control, resulting in tight packaging of DNA in the nucleosome. Additionally, reversible lysine acetylation is an important regulatory process for non-histone proteins. Thus, compounds that are able to modulate HDAC have important therapeutic potential.
The natural products FK228 (Structure I) and Spiruchostatin A (Structure II) are depsipeptides that have been reported to have potential as HDAC inhibitors. The term depsipeptide describes a class of oligopeptides or polypeptides that have both ester and peptide links the chain.
FK228 is a cyclic depsipeptide containing 4 monomer units together with a cross-ring bridge. This compound, under the trade name of ROMIDEPSIN®, has been tested as a therapeutic in human trials and shown that it has valuable effects on a number of diseases.
Spiruchostatin A is a cyclic depsipeptide that is structurally related to FK228: it is a cyclic depsipeptide containing a tri-peptide, a statine unit and a cross-ring bridge.

However, because both FK228 and Spiruchostatin A are natural products, they are not amenable to optimization for use as a therapeutic agent.
Analogues of Spiruchostatin A are disclosed in PCT/GB2007/050709. They may have improved HDAC inhibitory properties with respect to Spiruchostatin A or FK228 or other drug-like properties that make them more useful as medicines. These compounds have the general structures shown in Structures III and IV wherein R1, R5, R7 and R9 are the same or different and represent hydrogen or an amino acid side chain moiety from either a natural or an unnatural amino acid, R2 and R6 are hydrogen, each R10 is the same or different and represents hydrogen or C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, Pr1 and Pr2 are the same or different and represent hydrogen or a thiol protecting group and Pr3 is hydrogen or an alcohol protecting group.

Analogues of FK228 are disclosed in WO2006/129105. They may have improved HDAC inhibitory properties with respect to FK228 or other drug-like properties that make them more useful as medicines. These compounds have the general structures shown in Structures V and VI wherein R1, R5, R7 and R9 are the same or different and represent hydrogen or an amino acid side chain moiety from either a natural or an unnatural amino acid, R2 and R6 are hydrogen, each R10 is the same or different and represents hydrogen or C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, and Pr1 and Pr2 are the same or different and represent hydrogen or a thiol protecting group.

Analogues of FK228 and Spiruchostatin A with modifications in the disulfide containing bridge are disclosed in WO 2008/062201.
Without being constrained by theory, it is believed that Structures VII and VIII are formed inside the cell from Structures I and II respectively, by reduction of the disulfide bond, and that the 4-thio-butyl-1-ene so formed is a critical part of the mechanism of action of the compound, forming a metallophile capable of binding Zinc in the active site of HDAC.

This concept is supported by the observation that FR-901375, a cyclic depsipeptide HDAC inhibitor with quite a different ring structure, has the same disulfide-containing bridge across the ring as is seen in FK228 and Spiruchostatin A.